KEAP1

Official Full Name

kelch like ECH associated protein 1

Organism

Homo sapiens

GeneID

9817

Background

This gene encodes a protein containing KELCH-1 like domains, as well as a BTB/POZ domain. Kelch-like ECH-associated protein 1 interacts with NF-E2-related factor 2 in a redox-sensitive manner and the dissociation of the proteins in the cytoplasm is followed by transportation of NF-E2-related factor 2 to the nucleus. This interaction results in the expression of the catalytic subunit of gamma-glutamylcysteine synthetase. Two alternatively spliced transcript variants encoding the same isoform have been found for this gene. [provided by RefSeq, Jul 2008]

Synonyms

INrf2; KLHL19;

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Detailed Information

Keap1 belongs to the BTB-Kelch protein family, which contains 50 members and is named Kelch-like 1-42 (KLHL1-42) or Kelch and BTB domains 1-14 (KBTBD1-14). All of these proteins are assembled with Cullin 3 (Cul3 in this case) and Rbx1 to form a multi-subunit cullin-ring ligase (CRL) for protein ubiquitination. Keap1 is classified as KLHL19 and contains three domains spanning approximately 611 amino acids. The N-terminal BTB domain is named after the Drosophila proteins Broad complex, Tramtrack, and Bric à brac, in which it was first identified. The BTB domain mediates the homodimerization of Keap1 and contributes to its interaction with Cul3. A further Cul3 interaction is provided by a 3-box motif that forms the proximal portion of the central insertion region (IVR domain). The C-terminal Kelch domain is required for substrate capture and can bind separately to the ETGE or DLG motifs of Nrf2 (nuclear factor erythrocyte 2-related factor 2).

Figure 1. Domain architecture of the Keap1 proteins.

When it comes to Keap1, you can't help but mention Nrf2. In recent years, the research on Keap1 is basically around Keap1 and Nrf2. Mammalian cells are often exposed to oxidative stress, which is considered to be the most important and ubiquitous cause of tumors, metabolism, cardiovascular, neurodegenerative diseases and many other chronic diseases. To deal with the deleterious effects of oxidative stresses, cells have evolved an elaborate and powerful cellular defense machinery against reactive oxygen species (ROS). The core of this cellular defense mechanism is the transcription factor Nrf2 and its negative regulator kelch-like ECH-related protein 1 (Keap1). Under basal conditions, Keap1 acts as an adaptor between Nrf2 and the ubiquitinated ligase Cullin-3 (Cul3) and promotes proteasomal degradation of Nrf2. Upon modification of specific thiols, Keap1 allows Nrf2 to translocate into nucleus and activate the expression of a wide array of antioxidative metabolizing/detoxifying and many other genes by binding to the antioxidant response element (ARE) in their regulatory regions.

Inflammation and oxidative stress are constantly occurring in the body. As a key defense mechanism in vivo, the dysregulation of the Keap1–Nrf2–ARE pathway is implicated in numerous diseases. Ferroptosis is a form of cell death that has recently been reported during exposure to erastin and other FDA-approved (Approved by the Food and Drug Administration) drugs, including sorafenib. The p62-Keap1-Nrf2 antioxidant signaling pathway is a key negative regulator of iron turnover in HCC cells (hepatoma cells) through transcriptional activation of genes involved in ROS and iron metabolism. Inhibition of the p62-Keap1-Nrf2 pathway significantly enhanced the anticancer activity of erastin and sorafenib in HCC cells in vitro and in vivo. In contrast, ferroptosis involves generation of iron dependent accumulation of lipid ROS, which can be pharmacologically inhibited by iron chelators and lipid peroxidation inhibitors. The p62-Keap1-Nrf2 antioxidant signaling pathway is involved in the protection of iron transfer in HCC cells. P62 expression prevents Nrf2 degradation and enhances subsequent Nrf2 nuclear accumulation by inactivation of Keap1. In conclusion, activation of Nrf2 inhibits iron sag in HCC cells, but first requires p62-mediated Keap1 degradation to promote Nrf2 activation.

References:

Uruno A, et al . The Keap1–Nrf2 system and diabetes mellitus. Archives of Biochemistry and Biophysics, 2015, 566:76-84.
Leinonen H M, et al. Role of the Keap1-Nrf2 Pathway in Cancer. Advances in Cancer Research, 2014, 122C(4):281-320.
Suzuki T, et al. Molecular basis of the Keap1–Nrf2 system. Free Radical Biology and Medicine, 2015, 88:S0891584915002749.
Canning P, et al. Structural basis of Keap1 interactions with Nrf2. Free Radical Biology and Medicine, 2015, 88:101-107.
Cheng D, et al. Regulation of Keap1–Nrf2 signaling: The role of epigenetics. Current Opinion in Toxicology, 2016, 1:134-138.

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